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Titolo:
MOLECULAR-BASIS FOR THYMIDINE MODULATION OF THE EFFICACY AND TOXICITYOF ALKYLATING-AGENTS
Autore:
HWU WJP; MOZDZIESZ DE;
Indirizzi:
YALE UNIV,SCH MED,DEPT MED,333 CEDAR ST NEW HAVEN CT 06520 YALE UNIV,SCH MED,YALE COMPREHENS CANC CTR,DEPT PHARMACOL NEW HAVEN CT 06520
Titolo Testata:
Pharmacology & therapeutics
fascicolo: 1-3, volume: 76, anno: 1997,
pagine: 101 - 116
SICI:
0163-7258(1997)76:1-3<101:MFTMOT>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
HIGH-DOSE THYMIDINE; ADVANCED MALIGNANT-MELANOMA; PHASE-I; PYRIMIDINE DEOXYRIBONUCLEOSIDES; ANTINEOPLASTIC AGENTS; CELL-DIFFERENTIATION; ANTITUMOR-ACTIVITY; ADP-RIBOSYLATION; TUMOR-CELLS; 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA;
Keywords:
THYMIDINE; 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA (BCNU); DACARBAZINE (DTIC); BIOMODULATOR; ANTITUMOR RESPONSE; CHEMOTHERAPY TOXICITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
79
Recensione:
Indirizzi per estratti:
Citazione:
W.J.P. Hwu e D.E. Mozdziesz, "MOLECULAR-BASIS FOR THYMIDINE MODULATION OF THE EFFICACY AND TOXICITYOF ALKYLATING-AGENTS", Pharmacology & therapeutics, 76(1-3), 1997, pp. 101-116

Abstract

The antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)in mice previously was shown to be markedly enhanced by co-administration of thymidine. We have examined the cellular mechanisms underlyingthe augmentation effect of thymidine. It was found that thymidine didnot increase the cytotoxicity of BCNU for B16/F10 melanoma or L1210 leukemia cells in vitro. Instead, thymidine appeared to augment the activity of tumor-specific cytotoxic T-cells in tumor-bearing mice, whichspecifically rejected a secondary challenge with the B16/F10 tumor. Thus, development of an antitumor immune response is facilitated by thymidine in BCNU-induced immunosuppressed mice. These preclinical studies suggested that combination therapy with alkylating agents and thymidine may be a more efficacious and less toxic anticancer therapy. The potential efficacy of the sequential administration of dacarbazine (DTIC), BCNU, and thymidine in patients with advanced malignant melanoma was investigated. As predicted from animal studies, sequential administration of DTIC, BCNU, and thymidine is a relatively nontoxic therapy for metastatic melanoma. This treatment induced durable responses in upto 35% of patients, and hence is superior to many commonly used toxiccombination chemotherapies. The mechanism of action, although not well characterized, is thought to be mediated through protection of the cellular immune process, as well as organ function, from alkylating agent toxicity through modulation of DNA repair enzymes such as O-6-alkylguanine-DNA alkyltransferase in normal tissue. Thus, thymidine is a biomodulator, which not only protects patients from hematologic, pulmonary, and hepatic toxicities associated with DTIC and BCNU chemotherapy,but also potentiates therapeutic efficacy. (C) 1997 Elsevier Science Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/09/20 alle ore 00:57:18